Recently, non-viral gene therapy continues to attract much attention due to increasing safety concerns and deleterious adverse events of viral vectors in clinical trials. The goal of this application is to design a functional, pancreas-targeting polymeric gene carrier to carry therapeutic plasmid DNAs for efficient type-1 diabetes gene therapy. A new class of biodegradable polymeric carriers based on poly(disulfide amine)s are proposed. Poly(disulfide amine)s have demonstrated higher transfection efficiency with much lower cytotoxicity compared to conventional high molecular weight polyethylenimine. These biodegradable and biocompatible poly(disulfide amine) gene carriers will be modified for active targeting by PEG conjugation bearing ephrine, a pancreas-specific targeting ligand. The use of PEG is two-fold to first provide coronal ephrine presentation and for polyplex stability following intravenous administration. Type-1 diabetes is a deadly disease with numerous deleterious and deadly sequelae; yet, years of mechanistic research has yet to provide a clear pathogenic understanding. It is reported that NKG2D-mediated death of islet 2-cells plays an important role in the pathogenesis of type-1 diabetes. Recent reports demonstrate that tumors prevent attack by the host immune system by secreting soluble ligands for the receptor, NKG2D, expressed in several activated lymphocytes. This ability of tumors to disguise itself leads to reduced cell-cell contact-mediated cytocidal activity of the lymphocytes. Hence, exploiting this tumor model behavior we hypothesize that islet 2-cells secreting this soluble ligand for NKG2, sRAE-1, will protect pancreatic islets from autoimmune lymphocytes. In conjunction with ephrine-targeted poly(disulfide amine) gene carriers to the pancreas, we hypothesize that a pancreas-specific rat insulin promoter (RIP) will provide even tighter spatial and temporal control over sRAE-1 expression. To enhance transcription of sRAE-1, a two-step transcriptional amplification (TSTA) will be used. This novel approach to treat type-1 diabetes will be evaluated in vitro and in vivo with type-1 diabetic, non-obese (NOD) mice.